MTHFR Mutation

The MTHFR gene carries the instructions for methylenetetrahydrofolate reductase, an enzyme that turns one form of folate (vitamin B9) into 5-methyltetrahydrofolate, the main form of folate in the blood. That form is needed to recycle the amino acid homocysteine back into methionine. An "MTHFR mutation" almost always means one of two common variants: C677T, where a C is replaced by a T at position 677 of the gene, and A1298C, where an A is replaced by a C at position 1298. These variants are better described as common gene differences than as mutations. In the 1995 study that identified C677T, about 38% of the chromosomes tested carried it, and more people in the United States have one or two copies than have none. Having two copies (the TT genotype) makes the enzyme less stable and less active, and people with TT have higher homocysteine on average. Having one copy (CT, or heterozygous) has a much smaller effect, and the CDC says there isn't enough evidence that A1298C on its own meaningfully changes how the body handles folate. What a higher homocysteine level means for health has been tested in very large studies, and most of the early alarm has not held up. A meta-analysis of 48,175 people with coronary heart disease found no extra risk with the TT genotype, the largest single study of blood clots (4,375 patients) found none either, and the American College of Medical Genetics advises against MTHFR testing as part of a routine work-up for clotting disorders. Links with stroke, spina bifida and pregnancy loss appear in some data but are modest, and for stroke the link largely disappears where diets are rich in folate. The practical upshot is simple: the variant itself needs no treatment. Good folate intake matters more than genotype, folic acid works for carriers, and anyone who could become pregnant should take 400 mcg of folic acid daily whatever their MTHFR result. One targeted use has trial support: in people with the TT genotype and high blood pressure, low-dose riboflavin (vitamin B2) lowered blood pressure in trials from one research group.

• •Usually none at all
• •Higher homocysteine on testing (TT)
• •Slightly lower blood folate (TT)

• •Inheriting one C677T copy (CT genotype)
• •Inheriting two C677T copies (TT genotype)
• •Inheriting the A1298C variant
• •Carrying one C677T and one A1298C copy
• •Low folate intake magnifies the effect
• •Low riboflavin status magnifies the effect

The variants are inherited: everyone carries two copies of the MTHFR gene, one from each parent, so a person can be CC (no C677T copies), CT (one copy) or TT (two copies). The C677T change makes the enzyme heat-sensitive (thermolabile), which lowers its activity, so less folate is converted into the form used to recycle homocysteine. Whether this matters depends largely on folate intake. In low-folate regions (Asia), people with TT had homocysteine about 3.1 umol/L higher than people with CC; in regions with folate fortification (America, Australia, New Zealand) the gap was close to zero (0.13 umol/L). Low riboflavin status also matters, because riboflavin is the enzyme's cofactor. A rare, separate disorder, severe MTHFR deficiency caused by at least 40 other mutations, leads to homocystinuria; it is not the same thing as carrying C677T or A1298C.